Genomic stability is vital to the health of the individual and the preservation of the species. This stability can be threatened by DNA damage from endogenous and exogenous sources. However, mutations, which are heritable sequence changes in the DNA, can also arise as a result of errors made during replication of undamaged DNA. Recently an entirely new family of error-prone DNA polymerases has been discovered. Found in all three domains of life, these polymerases are beneficial because they can replicate past DNA lesions, but they are also potentially detrimental because they make frequent errors, even on undamaged DNA. If the activities of these polymerases are not controlled, they could be a potent source of the mutations that lead to genetic disorders such as cancer. The hypothesis underlying the proposed research is that cells can and must control the activities of their error-prone DNA polymerases. To test this hypothesis, pathways that control the activity of E. colts error-prone DNA polymerase IV (Pol IV) will be found and characterized. The specific aims are: (1) to identify new regulatory factors that affect the mutagenic activity of Pol IV; (2) to characterize the proteins and pathways regulating Pol IV levels or activity; and, (3) to further characterize the regulatory factors that are already identified. Because Pol IV is a close homologue of eukaryotic error-prone DNA polymerases, higher organisms, including humans, may use similar control mechanisms.